Particles containing an opioid receptor antagonist and methods of use

ABSTRACT

Particles comprising an opioid receptor antagonist as well as methods of their use and methods of their preparation are provided herein. Such particles may be used for treating and preventing opioid-induced side effects in patients, and may be provided to chronic opioid users as well.

The present application claims the benefit of priority to U.S.Provisional Application No. 61/077,242, filed Jul. 1, 2008 the entirecontents of this application being incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the fields of opioid receptorantagonists and drug delivery. In general, particles comprising anopioid receptor antagonist are described along with methods of theiruse.

2. Description of Related Art

Opioids are effective analgesics. However, their use is associated witha number of undesirable side effects. One such effect is constipation.Opioid-induced changes in gastrointestinal motility are almost universalwhen these drugs are used to treat pain, and at times may limit theiruse, leaving the patient in pain. Common treatments of bulking agentsand laxatives have limited efficacy and may be associated with sideeffects such as electrolyte imbalances.

One treatment for opioid side effects is the use of opioid receptorantagonists which cross the blood-brain-barrier, or which areadministered directly into the central nervous system. Opioid receptorantagonists such as naltrexone and naloxone have been administeredintramuscularly or orally to treat opioid induced side effects.Naltrexone and naloxone are highly lipid soluble and rapidly diffuseacross biological membranes, including the blood-brain barrier. However,naltrexone, naloxone, nalmefene, and other opioid receptor antagonistswhich may reverse many opioid side effects have a narrow therapeuticwindow before they are observed to reverse the desired analgesic effectof the opioid being used.

Many quaternary amine opioid receptor antagonist derivatives, such asmethylnaltrexone (MNTX), do not reduce the analgesic effect of opioidswhen administered peripheral to the central nervous system. Thesequaternary amine opioid receptor antagonist derivatives, which have arelatively higher polarity and reduced lipid solubility when compared tothe tertiary forms of the drugs, were specifically developed to nottraverse the blood-brain barrier or to traverse it at a greatly reducedrate. However, high levels of MNTX in the plasma can lead to undesirableside effects such as orthostatic hypotension.

In April 2008, the United States FDA approved the use ofmethylnaltrexone bromide (Relistor™) as a subcutaneous injection to helprestore bowel function in patients with late-stage, advanced illness whoare receiving opioids on a continuous basis to help alleviate theirpain. In particular, the drug is designed to alleviate constipation inpatients who have not successfully responded to laxative therapy.

Alternative methods of providing methylnaltrexone and other opioidreceptor antagonists to patients are desirable, such as methods thatallow lower doses of the antagonist to be delivered but with comparableefficacy, and methods less intrusive than subcutaneous injection.

SUMMARY OF THE INVENTION

The present invention provides methods and compositions involvingparticles comprising an opioid receptor antagonist. In some embodiments,these particles allow for enhanced effects on opioid-induced boweldysfunction and other indications. For example, particles of the presentinvention may result in improved absorption of the opioid receptorantagonist into the circulatory system compared to traditionalformulations, thus resulting in a decrease in the dose required to reachtherapeutic plasma levels. The particles may also be employed inpreventative methods as well, such as to prevent opioid-induced sideeffects. Moreover, the opioid responsible for the opioid-induced effectsmay be an exogenously administered opioid, or an endogenous opioid thatis produced by a patient in response to, for example, abdominal surgery.Chronic opioid users may also benefit from receiving particles of thepresent invention. Particles may comprise enteric coatings and/ortime-release agents to assist in targeted or controlled absorption ofthe opioid receptor antagonist.

As explained in further detail below, a particle may comprise only onetype of particle (“homoparticulate”), or a particle may comprise two ormore types of particles (“heteroparticulate”). Accordingly, the term“particle” encompasses both homo- and heteroparticulate particles. A“type” of particle refers to a particle comprising a particular set ofingredients. Thus, two different types of particles will have twodifferent sets of ingredients (e.g., one particle comprises an opioidreceptor antagonist and one particle does not). If two particles containthe same ingredients but the ratio of ingredients differs, the twoparticles are still considered to be of the same “type.”

As will be explained, it is to be understood that a particle of thepresent invention comprising an opioid receptor antagonist may include,but is not limited to, a homoparticulate particle, a heteroparticulateparticle, a particle that comprises a single particle, a particle thatcomprises two or more particles, an enterically coated particle, aparticle comprising a time-release agent, or a particle comprising anyother property or ingredient described herein or any combination ofthese properties or ingredients, except for combinations of particleswhose definitions (provided below) are mutually exclusive (e.g., aparticle cannot simultaneously be a homoparticulate particle and aheteroparticulate particle). Any of these particles may be comprised ina pharmaceutical composition, as described herein, and/or may beemployed in any methods of making, administration, and/or use asdescribed herein.

Accordingly, one general aspect of the present invention contemplates aparticle comprising an opioid receptor antagonist. Opioid receptorantagonists are described herein. Another general aspect of the presentinvention contemplates a particle comprising an opioid receptorantagonist and chitosan. Yet another general aspect of the presentinvention contemplates an enterically coated particle that comprises atleast one opioid receptor antagonist. Any particle discussed herein mayfurther comprise at least one additive. Such additives are describedherein. The diameter of any particle described herein may be betweenabout 30-1000 nm or higher, as that range is described herein. Incertain embodiments, a homoparticulate particle is contemplated. Incertain embodiments, a heteroparticulate particle is contemplated.

An opioid receptor antagonist that is comprised in any particle of thepresent invention may be, for example, a peripheral opioid antagonist.In certain embodiments, the opioid receptor antagonist may be aquaternary or tertiary morphinan derivative, apiperidine-N-alkylcarboxylate, a carboxy-normorphinan derivative, or aquaternary benzomorphan. The quaternary morphinan may be, for example, aquaternary salt of N-methylnaltrexone, N-methylnaloxone,N-methylnalorphine, N-diallylnormorphine, N-allyllevellorphan, orN-methylnalmefene. In particular embodiments, the peripheral opioidreceptor antagonist is methylnaltrexone. In certain embodiments, aparticle comprises two or more opioid receptor antagonists. In certainembodiments, the weight percentage of total opioid receptor antagonistin the particle ranges from about, at most about, or at least about0.1-30%. In certain embodiments, the weight percentage of total opioidreceptor antagonist is about 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%,5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%,20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%, or any rangederivable therein. The weight percentage of total opioid receptorantagonist in the particle may range higher than 30%, in certainembodiments. In certain embodiments, the weight percentage may be about,at least about, or at most about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,75%, 80%, 85%, 90%, 95%, or 99%, or any range derivable therein.

As noted above, a particle of the present invention may comprise anadditive. Additives that may be employed are described herein. Anadditive may comprise a polymer. An additive may comprise, for example,a polysaccharide. An additive may comprise, for example, apolyphosphate. In certain embodiments, at least one additive is ahydrophobic additive. Hydrophobic additives are defined herein. Incertain embodiments, at least one additive is a hydrophilic additive.Hydrophilic additives are defined herein. More than one additive may beemployed, as described herein. For example, a particle may comprise atleast two hydrophilic additives. A hydrophilic additive may, forexample, be positively charged at acidic and neutral pH. Acidic pHrefers to a pH of less than 7.0. In certain embodiments, “acidic pH”refers to about or at most about 6.5, 6.0, 5.5, 5.0, 4.5, 4.0, 3.5, 3.0,2.5, 2.0, 1.5, 1.0, 0.5 or lower, or any range derivable therein. Ahydrophilic additive that is positively charged at acidic and neutral pHmay be, for example, chitosan. Neutral pH refers to a pH of about 7.0.In certain embodiments, a hydrophilic additive may be negatively chargedat basic and neutral pH. As used herein, a basic pH refers to a pH ofgreater than 7.0. In certain embodiments, “basic pH” refers to about orat least about 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13,13.5, 14, or higher, or any range derivable therein. A hydrophilicadditive may be negatively charged at acidic and neutral pH, in certainembodiments. Such an additive may be, for example, a polyphosphate, suchas pentasodium tripolyphosphate (TPP). In certain embodiments, at leastone hydrophilic additive is a hydrophilic additive that is positivelycharged at acidic and neutral pH, and at least one second hydrophilicadditive is further defined as a hydrophilic additive that is negativelycharged at acidic and neutral pH. In certain embodiments, twohydrophilic additives employed in a particle of the present inventionare chitosan and TPP.

Ratios of additives that may be used in particles of the presentinvention are described herein. For example, the ratio of chitosan:TPPmay range between about 5:9 to about 50:9 (w/w). In certain embodiments,the ratio of chitosan:TPP:opioid receptor antagonist is between about5:9:4 to 50:9:32 (w/w/w). In certain embodiments, the ratio ofchitosan:TPP:opioid receptor antagonist is between about 5:9:4 to50:9:32 (w/w/w). In certain embodiments, the ratio ofchitosan:TPP:opioid receptor antagonist is between about 25:9:4 and25:9:32 (w/w/w). In certain embodiments, the ratio ofchitosan:TPP:opioid receptor antagonist is about 5:1.8:3.2 (w/w/w).

Any particle of the present invention may comprise an enteric agent, asdescribed herein. Accordingly, any particle of the present invention maybe comprised in an enteric coating to form an enterically coatedparticle. As noted above, an enterically coated particle may have adiameter of about 30-1000 nm, as that range is described herein. Incertain embodiments an enterically coated particle has a diameter ofabout 200-500 nm, as that range is described herein. An entericallycoated particle may comprise any polymer described herein, such as aEudragit® polymer (e.g., Eudragit® L100 or Eudragit® S100). An entericcoating may comprise, e.g., an acetylated monoglyceride, such as aMyvacet™ distilled acetylated monoglyceride. Such acetylatedmonoglycerides are known in the art, and include, e.g., Myvacet™ 9-45.Combinations of agents may be comprised within an enteric coating of thepresent invention. For example, a Eudragit® polymer and a Myvacet™distilled acetylated monoglyceride may be comprised in an entericcoating of an enterically coated particle of the present invention. Themesh fraction of the enterically coated particle may, in certainembodiments, range from about +40 to +90 mesh fraction (e.g., +40, +50,+60, +70, +80, +90, or any range derivable therein).

Pharmaceutical compositions that comprise a particle of the presentinvention are also described herein. Such pharmaceutical compositionstypically comprise at least one pharmaceutically acceptable carrier.Particles of the present invention may be comprised in a suspension andas such, the present invention contemplates pharmaceutical compositionscomprising a particle of the present invention, wherein the particle iscomprised in a suspension. Any pharmaceutical composition that comprisesa particle may be further defined as an orally administerablepharmaceutical composition. The orally administerable pharmaceuticalcomposition may, in certain embodiments, be comprised in a suspension orcapsule. The orally administerable pharmaceutical composition mayfurther comprise a flavoring agent. A pharmaceutical composition thatcomprises a particle of the present invention may be further defined asa time release pharmaceutical composition, wherein the time releasepharmaceutical composition is formulated to release the opioid receptorantagonist over time. Particles comprised in a pharmaceuticalcomposition may comprise any additive described herein, such as apolyanionic additive (e.g., pentasodium tripolyphosphate). Anothernon-limiting example of a pharmaceutical composition that comprises aparticle of the present invention is a pharmaceutical compositioncomprising a plurality of heteroparticulate particles and at least onepharmaceutical carrier, wherein the heteroparticulate particlescomprise: (a) an inner, larger particle comprising an opioid receptorantagonist; and (b) a plurality of outer, smaller particles comprisingat least one surfactant and at least one additive, wherein the averagediameter of the outer particles is between about 100-500 nm, as thatrange is described herein. In certain embodiments, the range of theaverage diameter of the outer particles is greater, such as betweenabout 100-1000 nm.

Methods of making particles comprising an opioid receptor antagonist arealso contemplated. For example, certain embodiments of the presentinvention contemplate a method of making one or more particles whereineach particle comprises an opioid receptor antagonist. The method maycomprise, for example: (a) dissolving an opioid receptor antagonist inwater to form a dissolved opioid receptor antagonist solution; (b)adding the dissolved opioid receptor antagonist solution to a solutioncomprising a first additive to form an opioid receptor antagonist/firstadditive solution; and (c) adding the opioid receptor antagonist/firstadditive solution to a solution comprising a second additive, such thatthe plurality of particles is made. Such methods may further comprise,e.g., stirring of the solution comprising the second additive as thedissolved opioid receptor antagonist/first additive solution is added.In certain embodiments, such methods further comprise (d) centrifugingthe suspension such that liquid therein is separated from the particlescomprising the opioid receptor antagonist; (e) removing the supernatant;and (e) lyophilizing the particles. Such methods may further compriseencapsulating the particles in an enteric coating. Enteric coatings aredescribed herein. The opioid receptor antagonist may be any opioidreceptor antagonist described herein.

As noted herein, a particle of the present invention that comprises anopioid receptor antagonist may be a heteroparticulate particle. Thepresent invention contemplates a heteroparticulate particle comprising:(a) an inner, optionally larger or optionally smaller particlecomprising an opioid receptor antagonist; and (b) an outer, optionallysmaller or optionally larger particle. The heteroparticulate particlemay comprise at least one surfactant and/or at least one additive, asthose terms are described herein. The diameter of a heteroparticulateparticle may range from 30-1000 nm or higher, as that range is describedherein. In certain embodiments, a heteroparticulate particle has adiameter of the outer particle that is between about 100-500 nm, as thatrange is described herein. In certain embodiments, a heteroparticulateparticle has a diameter of the outer particle that is between about100-1000 nm. The inner, larger particle may be further defined as amicroparticle. The inner particle may be a nanoparticle. The inner,larger particle of part (a) may further comprise a loading agent.Loading agents are described herein. A loading agent may comprise, e.g.,SiO₂. The loading agent may be further defined as, e.g., Aerosil® 200.In certain embodiments, the inner, larger particle comprises a core ofthe opioid receptor antagonist coated by a plurality of outer particles.In certain embodiments, the outer particles in a heteroparticulateparticle comprise an opioid receptor antagonist. In certain embodiments,one or more outer, smaller particles of a heteroparticulate particle isformulated as an enteric coating.

Any particle of the present invention may comprise a surfactant.Surfactants are described herein. For example, a surfactant may comprisea phosphatidylcholine. Phosphatidylcholines are described herein. Asurfactant may be, for example, Epikuron 170®. A surfactant may be anonionic surfactant, such as Tween® 80.

Any particle of the present invention may comprise a time-release agent.Time-release agents are described herein. In certain embodiments, theouter, smaller particle of a heteroparticulate particle is formulatedwith a time-release agent that permits release of an opioid receptorantagonist over time. Such a time-release agent may be, e.g., apoly(caprolactone).

Another general aspect of the present invention contemplates aheteroparticulate particle comprising: (a) an inner phase comprising onelarger particle, wherein the larger particle comprises an opioidreceptor antagonist and a loading agent; and (b) an outer phasecomprising a plurality of smaller particles, wherein each smallerparticle comprises Epikuron 170®, Tween® 80, a poly(caprolactone)polymer and/or a Eudragit® polymer.

Also contemplated are methods of making a heteroparticulate particlecomprising an opioid receptor antagonist. Such methods may comprise, forexample, (a) preparing an aqueous suspension comprising a plurality offirst particles; (b) dispersing at least one second particle comprisingan opioid receptor antagonist into the aqueous suspension comprising aplurality of first particles; and (c) spray-drying the product of step(b), wherein the diameter of the second particle is larger than theaverage diameter of the plurality of first particles. Such methods mayfurther comprise, e.g., concentrating the aqueous suspension comprisinga plurality of first particles. The aqueous suspension comprising aplurality of first particles may comprise: (a) at least two surfactants,wherein one surfactant is dissolved in an aqueous solution; (b) at leasttwo additives, and (c) an organic solvent. In certain embodiments, theaverage diameter of the plurality of outer particles is about 100-500nm, as that range is described herein. In certain embodiments, theaverage diameter of the plurality of outer particles is about 100-1000nm.

Methods of administering particles of the present invention are alsocontemplated, and such methods are described herein. For example, amethod comprising administering a particle comprising an opioid receptorantagonist and at least one additive to a patient, wherein the particleis either (a) a particle having a diameter of about 30-1000 nm, as thatrange is described herein; or (b) a heteroparticulate particle having aninner particle and an outer particle, wherein the inner particlecomprises the opioid receptor antagonist and wherein the diameter of theouter particle is about 100-500 nm, as that range is described herein,is contemplated. In certain embodiments, the diameter of the outerparticle is greater, such as between about 100-1000 nm. Any particle ofthe present invention may be employed in such methods. As discussedherein, such administration may be, e.g., orally, intraadiposally,intraarterially, intraarticularly, intradermally, intralesionally,intramuscularly, intranasally, intraocularally, intraperitoneally,intrapleurally, intrarectally, intrathecally, intratracheally,intraumbilically, intravenously, intravesicularly, intravitreally,liposomally, locally, mucosally, parenterally, rectally,subconjunctival, subcutaneously, sublingually, topically, transbuccally,transdermally, in creams, in lipid compositions, via a catheter, via alavage, via continuous infusion, via infusion, via inhalation, viainjection, via local delivery, via localized perfusion, bathing targetcells directly, or any combination thereof. In particular embodiments,the administration is orally, intravenously, or via injection. The outerparticles of the heteroparticulate particle may be further defined as aplurality of outer particles. The particle may be formulated to releasethe opioid receptor antagonist over time.

Patients or subjects of any appropriate method described herein aredescribed below. For example, a patient may be suffering from or may beat risk of suffering from constipation, dysphoria, pruritus, or urinaryretention. In certain embodiments, the patient is suffering from or isat risk of suffering a disorder selected from ileus, post-operativeileus, paralytic ileus, post-partum ileus, gastrointestinal dysfunctiondeveloping following abdominal surgery, and idiopathic constipation. Incertain embodiments, the patient is suffering from a disorder mediatedby opioid receptor activity selected from cancer involving angiogenesis,an inflammatory disorder, immune suppression, a cardiovascular disorder,chronic inflammation, chronic pain, sickle cell anemia, a vascularwound, retinopathy, decreased biliary secretion, decreased pancreaticsecretion, biliary spasm, and increased gastroesophageal reflux.

In particular embodiments, the present invention contemplates a methodcomprising administering to a patient a particle comprising at least oneopioid receptor antagonist and chitosan.

Other general aspects of the present invention contemplate a method forpreventing an opioid-induced side effect in a patient comprising orallyadministering an effective amount of a particle of the presentinvention, such as an enterically coated particle, comprising an opioidreceptor antagonist and at least one additive to the patient prior toadministration of an opioid, wherein, for example, the entericallycoated particle is either (a) a particle having a diameter of about30-1000 nm, as that range is described herein; or (b) aheteroparticulate particle having an inner particle and a plurality ofouter particles, wherein the inner particle comprises the opioidreceptor antagonist and wherein the outer particles each comprise anenteric agent and the average diameter of the outer particles is about100-500 nm, as that range is described herein. In certain embodiments,the range of the average diameter of the outer particles is greater,such as between about 100-1000 nm. The opioid induced side effect maycomprise, for example, at least one effect selected from inhibition ofintestinal motility, gastrointestinal dysfunction, constipation, bowelhypomotility, impaction, gastric hypomotility, inhibition of gastricmotility, inhibition of gastric emptying, delayed gastric emptying,incomplete evacuation, nausea, emesis, cutaneous flushing, bloating,abdominal distension, sweating, dysphoria, pruritis, and urinaryretention. In certain embodiments, the effective amount of theenterically coated particle comprising an opioid receptor antagonist isless than the effective amount of an aqueous solution of the opioidreceptor antagonist. In certain embodiments, the effective amount of theparticle, such as an enterically coated particle, comprising an opioidreceptor antagonist is less than the effective amount of an entericallycoated opioid receptor antagonist that is not comprised in anenterically coated particle. In certain embodiments, the effectiveamount of the enterically coated opioid receptor antagonist that is notcomprised in a particle is further defined as either: (a) an effectiveamount of an enterically coated opioid receptor antagonist that is notcomprised in a particle having a size of about 30-1000 nm, as that rangeis described herein; or (b) an effective amount of an enterically coatedopioid receptor antagonist that is not comprised in a heteroparticulateparticle having an inner particle and a plurality of outer particles,wherein the inner particle comprises the opioid receptor antagonist andwherein the outer particles each comprise an enteric agent and theaverage diameter of the outer particles is about 100-500 nm. In certainembodiments, the range of the average diameter of the outer particles isgreater, such as between about 100-1000 nm.

Dosages of particles of the present invention are described herein. Incertain embodiments of any method described herein, the dosage of aparticle comprising an opioid receptor antagonist, such as anenterically coated particle, is about 0.1-10 mg/kg body weight, as thatrange is described herein.

Also contemplated are methods for treating an opioid induced side effectcomprising administering, e.g., orally administering, an effectiveamount of a particle, such as an enterically coated particle, comprisingan opioid receptor antagonist to a patient subsequent to administrationof an opioid. The particle may be, for example, either (a) a particlehaving a diameter of about 30-1000 nm, as that range is describedherein; or (b) a heteroparticulate particle having an inner particle anda plurality of outer particles, wherein the inner particle comprises theopioid receptor antagonist and wherein the outer particles each comprisean enteric agent and the average diameter of the outer particles isabout 100-500 nm, as that range is described herein. In certainembodiments, the range of the average diameter of the outer particles isgreater, such as between about 100-1000 nm. In certain embodiments, theeffective amount of the enterically coated particle comprising an opioidreceptor antagonist is less than the effective amount of an aqueoussolution of the opioid receptor antagonist. In certain embodiments, theeffective amount of the enterically coated particle comprising an opioidreceptor antagonist is less than the effective amount of an entericallycoated opioid receptor antagonist that is not comprised in a particle.

Methods for treating gastrointestinal dysfunction following abdominalsurgery comprising administering a particle of the present invention toa patient are contemplated, such as methods comprising orallyadministering an effective amount of an enterically coated particlecomprising an opioid receptor antagonist to a patient, wherein thedysfunction is treated, wherein the particle is either: (a) a particlehaving a diameter of about 30-1000 nm, as that range is describedherein; or (b) a heteroparticulate particle having an inner particle anda plurality of outer particles, wherein the inner particle comprises theopioid receptor antagonist and wherein the outer particles each comprisean enteric agent and the average diameter of the outer particles isabout 100-500 nm, as that range is described herein. In certainembodiments, the range of the average diameter of the outer particles isgreater, such as between about 100-1000 nm.

Methods for preventing inhibition of gastrointestinal motility in apatient are also contemplated, such as methods for preventing inhibitionof gastrointestinal motility in a patient prior to the patient receivingan opioid for pain resulting from surgery comprising administering aneffective amount of a particle of the present invention, such as anenterically coated particle, comprising an opioid receptor antagonist tothe patient, wherein the particle is either (a) a particle having adiameter of about 30-1000 nm, as that range is described herein; or (b)a heteroparticulate particle having an inner particle and a plurality ofouter particles, wherein the inner particle comprises the opioidreceptor antagonist and wherein the outer particles each comprise anenteric agent and the average diameter of the outer particles is about100-500 nm, as that range is described herein. In certain embodiments,the range of the average diameter of the outer particles is greater,such as between about 100-1000 nm.

Another general aspect of the present invention contemplates a methodfor treating inhibition of gastrointestinal motility in a patientreceiving an opioid for pain resulting from surgery comprisingadministering an effective amount of a particle of the presentinvention, such as an enterically coated particle, comprising an opioidreceptor antagonist to the patient. The particle may be, for example,either: (a) a particle having a diameter of about 30-1000 nm, as thatrange is described herein; or (b) a heteroparticulate particle having aninner particle and a plurality of outer particles, wherein the innerparticle comprises the opioid receptor antagonist and wherein the outerparticles each comprise an enteric agent and the average diameter of theouter particles is about 100-500 nm, as that range is described herein.In certain embodiments, the range of the average diameter of the outerparticles is greater, such as between about 100-1000 nm.

Also contemplated are methods of preventing or treating anopioid-induced side effect in a chronic opioid patient, comprisingadministering an effective amount of a particle of the presentinvention, such as an enterically coated particle comprising an opioidreceptor antagonist, to the patient. The particle may be, for example,either: (a) a particle having a diameter of about 30-1000 nm, as thatrange is described herein; or (b) a heteroparticulate particle having aninner particle and a plurality of outer particles, wherein the innerparticle comprises the opioid receptor antagonist and wherein the outerparticles each comprise an enteric agent and the average diameter of theouter particles is about 100-500 nm, as that range is described herein.The side effect may be, for example, inhibition of intestinal motility,gastrointestinal dysfunction, constipation, bowel hypomotility,impaction, gastric hypomotility, inhibition of gastric motility,inhibition of gastric emptying, delayed gastric emptying, incompleteevacuation, nausea, emesis, cutaneous flushing, bloating, abdominaldistension, sweating, dysphoria, pruritis, or urinary retention.

In certain embodiments, following administration of a particlecomprising an opioid receptor antagonist, the opioid receptor antagonistis not substantially released in the stomach. As used herein, “theopioid receptor antagonist is not substantially released in the stomach”refers to a method wherein less than 10% of the administered opioidreceptor antagonist is released in the stomach. The reduced drugabsorption by the stomach may be measured using any technique known inthe art, such as by drug plasma level analysis using, e.g., HPLC, suchas C_(max), T_(max), and AUC (area under the curve). See, e.g., Yuan etal., 1997 and Yuan et al., 2000.

Any embodiment discussed with respect to one aspect of the inventionapplies to other aspects of the invention as well.

The embodiments in the Example section are understood to be embodimentsof the invention that are applicable to all aspects of the invention.

The term “effective,” as that term is used in the specification and/orclaims, means adequate to accomplish a desired, expected, or intendedresult.

“Therapeutically effective amount” means that amount which, whenadministered to a subject for treating a condition, disease, or sideeffect, is sufficient to effect such treatment for the condition,disease, or side effect.

“Treatment” or “treating” includes: (1) inhibiting a condition, disease,or side effect in a subject or patient experiencing or displaying thepathology or symptomatology of the condition, disease, or side effect(e.g., arresting further development of the pathology and/orsymptomatology), (2) ameliorating a condition, disease, or side effectin a subject or patient that is experiencing or displaying the pathologyor symptomatology of the condition, disease, or side effect (e.g.,reversing the pathology and/or symptomatology), and/or (3) effecting anymeasurable decrease in a condition, disease, or side effect in a subjector patient that is experiencing or displaying the pathology orsymptomatology of the condition, disease, or side effect.

“Prevention” or “preventing” includes: (1) inhibiting the onset of acondition, disease, or side effect in a subject or patient who may be atrisk and/or predisposed to the condition, disease, or side effect butdoes not yet experience or display any or all of the pathology orsymptomatology of the condition, disease, or side effect, and/or (2)slowing the onset of the pathology or symptomatology of the condition,disease, or side effect in a subject or patient which may be at riskand/or predisposed to the condition, disease, or side effect but doesnot yet experience or display any or all of the pathology orsymptomatology of the condition, disease, or side effect.

As used herein, the term “patient” or “subject” refers to a livingmammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat,mouse, rat, guinea pig, or transgenic species thereof. Non-limitingexamples of human subjects are adults, juveniles, children, infants andfetuses.

In certain embodiments, a patient is a chronic opioid user. Accordingly,aspects of the invention are useful to prevent or reduce the occurrenceor reoccurrence of an opioid-induced side effect in a chronic opioidpatient. A chronic opioid patient may be any of the following: a cancerpatient, an AIDS patient, or any other terminally ill patient. A chronicopioid patient may be a patient taking methadone. Chronic opioid use ischaracterized by the need for substantially higher levels of opioid toproduce the therapeutic benefit as a result of prior opioid use, as iswell known in the art. Chronic opioid use is also characterized by theneed for substantially lower levels of opioid antagonist to produce thetherapeutic benefit. Chronic opioid use as used herein includes dailyopioid treatment for a week or more or intermittent opioid use for atleast two weeks. In one embodiment, a patient, such as a chronic opioiduser, is taking a laxative and/or a stool softener.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts of compounds of thepresent invention which are pharmaceutically acceptable, as definedabove, and which possess the desired pharmacological activity.Accordingly, pharmaceutically acceptable salts of compounds of thepresent invention are contemplated herein. Such pharmaceuticallyacceptable salts include acid addition salts formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or with organic acids such as1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,2-naphthalenesulfonic acid, 3-phenylpropionic acid,4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid,aliphatic mono- and dicarboxylicacids, aliphatic sulfuric acids,aromatic sulfuric acids, benzenesulfonic acid, benzoic acid,camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid,cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid,glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid,heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid,laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelicacid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoicacid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substitutedalkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid,salicylic acid, stearic acid, succinic acid, tartaric acid,tertiarybutylacetic acid, trimethylacetic acid, and the like.Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike. It should be recognized that the particular anion or cationforming a part of any salt of this invention is not critical, so long asthe salt, as a whole, is pharmacologically acceptable. Additionalexamples of pharmaceutically acceptable salts and their methods ofpreparation and use are presented in Handbook of Pharmaceutical SaltsProperties, Selection and Use (P. H. Stahl & C. G. Wermuth eds., VerlagHelvetica Chimica Acta, 2002), which is incorporated herein byreference.

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method or composition of theinvention, and vice versa. Furthermore, compositions of the inventioncan be used to achieve methods of the invention.

It is also contemplated that any method described herein may bedescribed using Swiss-type use language.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive.

Throughout this application, the term “about” is used to indicate that avalue includes the standard deviation of error for the device or methodbeing employed to determine the value.

Following long-standing patent law, the words “a” and “an,” when used inconjunction with the word “comprising” in the claims or specification,denotes one or more, unless specifically noted.

The terms “comprise,” “have” and “include” are open-ended linking verbs.Any forms or tenses of one or more of these verbs, such as “comprises,”“comprising,” “has,” “having,” “includes” and “including,” are alsoopen-ended. For example, any method that “comprises,” “has” or“includes” one or more steps is not limited to possessing only those oneor more steps and also covers other unlisted steps.

Other objects, features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating specific embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

FIG. 1 shows methylnaltrexone (MNTX) plasma levels at the indicatedtimes after oral administration of MNTX, N1-MNTX, and N2-MNTX to rats.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS I. Opioid Receptor Antagonists

The opioid receptor antagonists of the present invention include bothcentrally and peripherally acting opioid receptor antagonists. Incertain embodiments, peripherally acting opioid receptor antagonists arecontemplated.

Opioid receptor antagonists form a class of compounds that can vary instructure while maintaining their antagonist properties. These compoundsinclude tertiary and quaternary morphinans, such as noroxymorphonederivatives; N-substituted piperidines, such aspiperidine-N-alkylcarboxylates, tertiary and quaternary benzomorphans,and tertiary and quaternary normorphinan derivatives, such as6-carboxy-normorphinan derivatives. Tertiary compound antagonists arefairly lipid soluble and cross the blood-brain barrier easily. Examplesof opioid receptor antagonists that cross the blood-brain barrier andare centrally (and peripherally) active include, e.g., naloxone,naltrexone (each of which is commercially available from BaxterPharmaceutical Products, Inc.), and nalmefene (available, e.g., fromDuPont Pharma). Peripherally restricted antagonists, on the other hand,are typically charged, polar, and/or of high molecular weight: theseproperties typically impede their crossing the blood-brain barrier.Methylnaltrexone is a quaternary derivative of the tertiary opioidreceptor antagonist, naltrexone. Addition of the methyl group tonaltrexone forms a compound with greater polarity and lower lipidsolubility. Thus, methylnaltrexone does not cross the blood-brainbarrier and has the potential for blocking the undesired adverse effectswhich are typically mediated by peripherally located receptors.

A peripheral opioid receptor antagonist suitable for use in theinvention may be a compound which is a quaternary morphinan derivative,such as a quaternary noroxymorphone of formula (I):

wherein R is alkyl, alkenyl, alkynyl, aryl, cycloalkyl-substitutedalkyl, or arylsubstituted alkyl, and X⁻ is the anion, such as achloride, bromide, iodide, or methylsulfate anion. The noroxymorphonederivatives of formula (I) can be prepared, for example, according tothe procedure in U.S. Pat. No. 4,176,186, which is incorporated hereinby reference; see also U.S. Pat. Nos. 4,719,215; 4,861,781; 5,102,887;5,972,954; and 6,274,591; U.S. Patent Application Nos. 2002/0028825 and2003/0022909; and PCT publication Nos. WO 99/22737 and WO 98/25613, allof which are hereby incorporated by reference.

A compound of formula (I) may be N-methylnaltrexone (or simplymethylnaltrexone), wherein R is cyclopropylmethyl as represented informula (II):

wherein X⁻ may be any pharmaceutically acceptable anion.Methylnaltrexone is a quaternary derivative of the μ-opioid receptorantagonist naltrexone. Methylnaltrexone exists as a salt (e.g.,N-methylnaltrexone bromide) and the terms “methylnaltrexone” or “MNTX”,as used herein, therefore embrace such salts. “Methylnaltrexone” or“MNTX” thus specifically includes, but is not limited to, bromide salts,chloride salts, iodide salts, carbonate salts, and sulfate salts ofmethylnaltrexone. Names used for the bromide salt of MNTX in theliterature, for example, include: methylnaltrexone bromide;N-methylnaltrexone bromide; naltrexone methobromide; naltrexone methylbromide; SC-37359; MRZ-2663-BR; andN-cyclopropylmethylnoroxy-morphine-methobromide. A compound of formula(I) may be S—N-methylnaltrexone.

Methylnaltrexone is commercially available from, e.g., MallinckrodtPharmaceuticals, St. Louis, Mo. Methylnaltrexone is provided as a whitecrystalline powder, freely soluble in water, typically as the bromidesalt. The compound as provided is 99.4% pure by reverse phase HPLC, andcontains less than 0.011% unquaternized naltrexone by the same method.Methylnaltrexone can be prepared as a sterile solution at aconcentration of, e.g., about 5 mg/mL.

Other suitable peripheral opioid receptor antagonists may includeN-substituted piperidines, such as piperidine-N-alkylcarboxylates asrepresented by formula (III):

wherein R¹ is hydrogen or alkyl; R² is hydrogen, alkyl, or alkenyl; R³is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, oraryl-substituted alkyl; R⁴ is hydrogen, alkyl, or alkenyl; A is OR⁵ orNR⁶R⁷; wherein R⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, oraryl-substituted alkyl; R⁶ is hydrogen or alkyl; R⁷ is hydrogen, alkyl,alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,cycloalkenyl-substituted alkyl or aryl-substituted alkyl, oralkylene-substituted B or together with the nitrogen atom to which theyare attached, R⁶ and R⁷ form a heterocyclic ring selected from pyrroleand piperidine; B is

wherein R⁸ is hydrogen or alkyl; R⁹ is hydrogen, alkyl, alkenyl, aryl,cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,cycloalkenyl-substituted alkyl or aryl-substituted alkyl or togetherwith the nitrogen atom to which they are attached, R⁸ and R⁹ form aheterocyclic ring selected from pyrrole and piperidine; W is OR¹⁰,NR¹¹R¹², or OE; wherein R¹⁰ is hydrogen, alkyl, alkenyl, cycloalkyl,cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substitutedalkenyl, or aryl-substituted alkyl; R¹¹ is hydrogen or alkyl; R¹² ishydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl,aryl-substituted alkyl, or alkylene-substituted C(═O)Y or, together withthe nitrogen atom to which they are attached, R¹¹ and R¹² form aheterocyclic ring selected from pyrrole and piperidine; E is

alkylene-substituted (C═O)D, or —R¹³OC(═O)R¹⁴; wherein R¹³ isalkyl-substituted alkylene; R¹⁴ is alkyl; D is OR¹⁵ or NR¹⁶R¹⁷; whereinR¹⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl substituted alkyl, oraryl-substituted alkyl; R¹⁶ is hydrogen, alkyl, alkenyl, aryl,aryl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkyl substitutedalkyl, or cycloalkenyl-substituted alkyl; R¹⁷ is hydrogen or alkyl or,together with the nitrogen atom to which they are attached, R¹⁶ and R¹⁷form a heterocyclic ring selected from the group consisting of pyrroleor piperidine; Y is OR¹⁸ or NR¹⁹R²⁰; wherein R¹⁸ is hydrogen, alkyl,alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R¹⁹ ishydrogen or alkyl; R²⁰ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substitutedalkyl, or aryl-substituted alkyl or, together with the nitrogen atom towhich they are attached, R¹⁹ and R²⁰ form a heterocyclic ring selectedfrom pyrrole and piperidine; R²¹ is hydrogen or alkyl; and n is 0 to 4.

Non-limiting examples of suitable N-substituted piperidines may beprepared as disclosed in U.S. Pat. Nos. 5,270,328; 6,451,806; and6,469,030, all of which are hereby incorporated by reference. Suchcompounds have moderately high molecular weights, a zwitterionic form,and a polarity that prevent penetration of the blood-brain barrier.

Particular piperidine-N-alkylcarbonylates includeN-alkylamino-3,4,4-substituted piperidines, such as alvimopanrepresented below as formula (IV):

Alvimopan is available from Adolor Corp., Exton, Pa.

Still other suitable peripheral opioid receptor antagonist compounds mayinclude quaternary benzomorphan compounds. Quaternary benzomorphancompounds may have the following formula (V):

wherein R¹ is hydrogen, acyl, or acetoxy; and R² is alkyl or alkenyl; Ris alkyl, alkenyl, or alkynyl and X⁻ is an anion, such as a chloride,bromide, iodide, or methylsulfate anion.

Specific quaternary derivatives of benzomorphan compounds that may beemployed in the methods of the invention include the following compoundsof formula (V):2′-hydroxy-5,9-dimethyl-2,2-diallyl-6,7-benzomorphanium-bromide;2′-hydroxy-5,9-dimethyl-2-n-propyl-2-allyl-6,7-benzomorphanium-bromide;2′-hydroxy-5,9-dimethyl-2-n-propyl-2-propargyl-6,7-benzomorphanium-bromide;and2′-acetoxy-5,9-dimethyl-2-n-propyl-2-allyl-6,7-benzomorphanium-bromide.

Other quaternary benzomorphan compounds that may be employed in methodsof the invention are described, for example, in U.S. Pat. No. 3,723,440,the entire disclosure of which is incorporated herein by reference.

Other peripheral opioid antagonists include 6-carboxy-normorphinanderivatives, particularly N-methyl-C-normorphinan derivatives, asdescribed in U.S. Published Application No. 2008/0064744, herebyincorporated in its entirety herein by reference, and including thecompound having the following formula (VI):

Other peripheral opioid antagonists may include polymer conjugates ofopioid antagonists, as described in U.S. Published Application No.2006/0105046, hereby incorporated by reference. Specific polymerconjugates include PEGylated naloxone and naltrexone.

The invention also encompasses administration of more than one opioidreceptor antagonist. Any combination of opioid receptor antagonists iscontemplated, including combinations of μ-opioid receptor antagonistsand combinations of g- and K-antagonists: for example, a combination ofmethylnaltrexone and alvimopan.

II. Particles of the Present Invention

Particles of the present invention comprise at least one opioid receptorantagonist. Certain properties of particles of the present invention arediscussed below.

A. Properties of Particles

As noted above, a particle may comprise only one type of particle(“homoparticulate”), or a particle may comprise two or more types ofparticles (“heteroparticulate”). Accordingly, the term “particle”encompasses both homo- and heteroparticulate particles. A “type” ofparticle refers to a particle comprising a particular set ofingredients. Thus, two different types of particles will have twodifferent sets of ingredients (e.g., one particle comprises an opioidreceptor antagonist and one particle does not). If two particles containthe same ingredients but the ratio of ingredients differs, the twoparticles are still considered to be of the same “type.”

A particle may comprise two or more particles and still be ahomoparticulate particle, wherein the two or more particles are of thesame type. For example, if a particle comprises two particles havingdifferent sizes, but the ingredients of each particle is the same, thenthe particle is a homoparticulate particle. If a particle comprises twoor more particles and the two or more particles are of different types,then the particle is a heteroparticulate particle regardless of thesizes of the particles. In any case, the two or more particles may be inphysical contact with each other such that the particles are foundtogether as a unit, wherein that unit is also considered a particle.

In certain embodiments, a particle may comprise a single particle. Incertain embodiments, a particle may comprise two or more particles.Accordingly, the term “particle” encompasses particles having only oneparticle, and particles having two or more particles. Regardingparticles comprising two or more particles, there may be an innerparticle and an outer particle. For example, an inner particle may be inphysical contact with one or more particles that are found on thesurface of the inner particle such that they are “outer” particles. Incertain embodiments, a plurality of outer particles coat the innerparticle. As used herein, “coat” refers to where a plurality of outerparticles are found on about, at most about, or at least about 90% ofthe surface of the inner particle. In certain embodiments, “coat” refersto where a plurality of outer particles are found on about, at mostabout, or at least about 90%, 95%, 99%, or more, of the surface of theinner particle, or any range derivable therein.

Generally speaking, then, any particle may be either a homoparticulateparticle or a heteroparticulate particle; any particle may comprise onlyone particle, wherein that particle may be either a homoparticulateparticle or a heteroparticulate particle; or any particle may comprisetwo or more particles, wherein each of the two or more particles may behomoparticulate particles or heteroparticulate particles, or acombination thereof.

The following schematic demonstrates non-limiting representations ofcross-sections of particles of the present invention, wherein eachindividual circle represents a particle, and each of A-S represents aparticle, and each particle may be the same type or may be differenttypes. These representations are not to scale and are merely forillustrative purposes. The particles are not necessarily spherical.

The diameters discussed herein apply to any type of particle describedherein, unless specifically noted otherwise. For example, ahomoparticulate particle, a heteroparticulate particle, or the particlesthat make up a homoparticulate particle or a heteroparticulate particlemay each have a diameter as discussed herein or, in the case of aplurality of particles, the plurality may have an average diameter ofthe values discussed herein. Any plurality of particles, as used herein,may all have about the same size diameter, or may together have anaverage diameter size.

In certain embodiments, the diameter of a particle of the presentinvention (or the average diameter of a plurality of particles) is about30-1000 nm. In certain embodiments, the diameter is about, at mostabout, or at least about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220,230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360,370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500,510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640,650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780,790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920,930, 940, 950, 960, 970, 980, 990 or 1000 nm or higher, or any rangederivable therein. In certain embodiments, a particle's diameter is lessthan 300 μm, or less than about 300 μm. In certain embodiments, adiameter is less than, or less than about 300, 275, 250, 200, 150, 100,75, 50, 10, 1, 0.75, 0.50, 0.25, 0.1, 0.01, or 0.001 μm, or any rangederivable therein. In certain embodiments, a particle's diameter is lessthan 300 μm, or less than about 300 μm, and greater than 1 nm (e.g.,less than, or less than about 300, 200, 100, 75, 50, 25, 10, 1, 0.1, or0.010 μm and greater than about 1 nm, or any range derivable therein).When a plurality of such particles is employed, the average diameter ofthe plurality of particles may be any of the values discussed in thisparagraph.

In certain embodiments, a particle may comprise an outer particle thatis found on the surface of an inner particle. Typically, a plurality ofouter particles are found on the surface and in some embodiments, aplurality of outer particles coat an individual inner particle. Incertain embodiments, the inner and outer particles comprise the sameingredients, such that the particle is a homoparticulate particle. Incertain embodiments, the inner particle comprises different ingredientsthan the outer particle, such that the particle is a heteroparticulateparticle. In certain embodiments, the inner and/or outer particle(s) isfurther defined as a microparticle or a nanoparticle (defined below). Incertain embodiments, a particle may comprise a smaller, outer particlethat is found on the surface of an individual larger, inner particle andtypically, a plurality of smaller particles coat the individual larger,inner particle. In certain embodiments, the diameter of the outerparticle ranges from about, at most about, or at least about 100-500 nm.For example, the diameter of the outer particle may be about, at leastabout, or at most about 100, 125, 150, 175, 200, 225, 250, 275, 300,325, 350, 375, 400, 425, 450, 475, 500 nm, or any range derivabletherein. In other embodiments, the range of the diameter of the outerparticle may be larger, such as about, at least about, or at most about100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425,450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775,800, 825, 850, 875, 900, 925, 950, 975 or 1000 nm, or any rangederivable therein. In certain embodiments wherein a plurality of outer,smaller particles coat an inner, larger particle, the average diameterof the plurality of outer, smaller particles ranges between about100-500 nm, as this range is described above. In certain embodiments, alarger, outer particle is found on the surface of an individual smaller,inner particle. In certain embodiments, a plurality of larger particlesare found on the surface of an individual smaller, inner particle. Incertain embodiments, a plurality of larger particles coat the surface ofan individual inner, smaller particle, wherein the meaning of “coat” isas described above.

In certain embodiments, particles of the present invention aremicroparticles. A microparticle is defined as a particle having adiameter of about 0.1-100 μm. In certain embodiments, the diameter of amicroparticle is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7. 0.8, 0.9, 1,1.5, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80,85, 90, 95 or 100 μm, or any range derivable therein. In certainembodiments, a particle comprises only one microparticle. In certainembodiments, a particle comprises or contains only a plurality ofmicroparticles. In certain embodiments, a microparticle may be comprisedin a homoparticulate particle. In certain embodiments, a microparticlemay be comprised in a heteroparticulate particle. In certainembodiments, at least one particle having a smaller diameter than themicroparticle is found on the surface of the microparticle. In certainembodiments, a plurality of smaller, outer particles coat themicroparticle. In certain embodiments, one or more larger, outerparticles coat the microparticle.

In certain embodiments, particles of the present invention arenanoparticles. A nanoparticle is defined as a particle having a diameterof about 1-100 nm. In certain embodiments, the diameter of ananoparticle is about 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55,60, 65, 70, 75, 80, 85, 90, 95 or 100 nm, or any range derivabletherein. In certain embodiments, a particle comprises only onenanoparticle. In certain embodiments, a particle comprises or containsonly a plurality of nanoparticles. In certain embodiments, ananoparticle may be comprised in a homoparticulate particle. In certainembodiments, a nanoparticle may be comprised in a heteroparticulateparticle. In certain embodiments, a plurality of nanoparticles coat aninner particle. In certain embodiments, a plurality of smaller, outernanoparticles coat a larger, inner particle. In certain embodiments, theinner particle of a homo- or heteroparticulate particle is ananoparticle; further, in certain embodiments, one or more larger orsmaller particles may be found on the surface of such a nanoparticle.For example, a plurality of larger or smaller particles may coat thesurface of a nanoparticle.

Particle diameters may also span the diameters described for micro- andnanoparticles (e.g., about 30-1000 nm, as that range is describedherein).

B. Additives

A variety of additives may be employed in the particles of the presentinvention. Additives may be characterized in more than one fashion. Incertain embodiments polymeric additives may be employed. In certainembodiments, polysaccharides may be employed. Homopolysaccharides and/orheteropolysaccharides are contemplated, as well as a variety ofmolecular weights (e.g., 10,000-150,000 g/mol). Non-limiting examples ofpolysaccharides include chitosan and cellulose (e.g., microcrystallinecellulose). Hydrophobic additives may be employed, in certainembodiments. A hydrophobic additive is defined as an additive having asurface energy that is less than 40 dynes/cm. Non-limiting examples ofhydrophobic additives include methacrylic acid copolymer, sodiumcarboxymethyl cellulose, cellulose acetate, ethyl cellulose (EC),hydroxypropyl methyl-cellulose acetate succinate (HPMCAS) and celluloseacetate phthalate (CAP). Hydrophilic additives are also contemplated, incertain embodiments. A hydrophilic additive is defined as an additivehaving a surface energy of ≧40 dynes/cm. Certain hydrophilic additivesare positively charged at acidic and neutral pH, and certain hydrophilicadditives are negatively charged at acidic and neutral pH. Non-limitingexamples of hydrophilic additives include, for example, chitosan and/orpolyphosphates such as tripolyphosphate (e.g., pentasodiumtripolyphosphate, TPP). Hydrophilic additives may also be eitherpolycationic and/or polyanionic. An example of a polyanionic additive isa polyphosphate, such as TPP. Yet another example of a polyanionicadditive is dextran sulfate (Sarmento et al., 2007).

When more than one additive is present in a particle, the ratio of theadditives in the particle may vary widely. For example, the ratio of oneadditive to any other additive in a particle may range from 1:1 to1:100,000 w/w. In certain embodiments, the w/w ratio is 1:1, 1:1.5, 1:2,1:2.5, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:25, 1:50, 1:100,1:250, 1:500, 1:750, 1:1000, 1:1500, 1:2000, 1:2500, 1:3000, 1:3500,1:4000, 1:4500, 1:5000, 1:5500, 1:6000, 1:6500, 1:7000, 1:7500, 1:8000;1:8500; 1:9000, 1:9500, 1:10,000, 1:25,000, 1:50,000, 1:75,000 or1:100,000, or any range derivable therein. In certain embodiments, theratio is 1:1. In certain embodiments, the ratio is 1:10 w/w. Forexample, where two additives are present in a particle, the ratiobetween the two additives may range from 1:1 to 1:100,000, or any rangederivable therein, as that range is described above. Where threeadditives are present, A, B and C, the w/w/w ratios of A:B:C may rangefrom 1:1:1 to 1:100, 000:1 to 1:100, 000:100,000 to 100, 000:1:1, to100, 000:100, 000:1 to 100, 000:1:100,000, to 1:1:100,000, or any rangederivable therein, as that range is described above. In certainembodiments, the ratio is 1:1:10 w/w/w. When four or more additives arecomprised within a particle of the present invention, the ratios may beadjusted similarly.

Further, when more than one additive is present in a particle, anycombination of additives discussed herein may be employed. For example,a polysaccharide and a hydrophobic additive may be employed. Apolysaccharide and a hydrophilic additive may be employed. A hydrophobicadditive and a hydrophilic additive may be employed. A polycationicand/or a polyanionic additive may be combined with each other or withany other additive described herein. The ratios of these additives maybe any ratio as described herein. Further, an additive may be combinedwith one or more surfactants, enteric agents, time-release agents, orloading agents, as described herein.

The ratio of additive to opioid receptor antagonist may also varywidely. For example, the ratio may range from 9:4 to 9:32additive:antagonist (w/w). The range may be broader, such as from 9:1 to9:128 w/w. In certain embodiments, the w/w ratio is 1.8:3.2.

Surfactants may also be employed in certain particles of the presentinvention. Surfactants are well-known in the art. Non-limiting examplesof surfactants include nonionic, cationic and anionic surfactants. Inparticular embodiments, nonionic surfactants are contemplated, such asTween® 80. Other nonionic Tween® products are also contemplated. Incertain embodiments, phosphatidylcholine surfactants may be employed,such as Epikuron 170®. Phosphatidylcholines, including those obtainedfrom egg, soy beans, or other plant sources or those that are partiallyor wholly synthetic, or of variable lipid chain length and unsaturation,are suitable for use in the present invention. Synthetic, semisyntheticand natural product phosphatidylcholines including, but not limited to,distearoylphosphatidylcholine (DSPC), hydrogenated soyphosphatidylcholine (HSPC), soy phosphatidylcholine (soy PC), eggphosphatidylcholine (egg PC), dioleoylphosphatidylcholine (DOPC),hydrogenated egg phosphatidylcholine (HEPC),dielaidoylphosphatidylcholine (DEPC), dipalmitoylphosphatidylcholine(DPPC) and dimyristoylphosphatidylcholine (DMPC) are suitablephosphatidylcholines for use in this invention. All of these agents arecommercially available. Combinations of surfactants may also be used.Moreover, any surfactant discussed herein may be combined with any oneor more additive, polymer, or enteric, time-release, or loading agent,as discussed throughout this application.

C. Enteric, Time-Release and Loading Agents

Any particle of the present invention may be enterically coated. Entericcoatings prevent or inhibit release of medication before the medicationreaches the small intestine. In particular, enteric coatingspreferentially dissolve in conditions having a higher pH than the acidicpH of the stomach, which typically has a pH of less than about 3.0(e.g., less than about 3.0, 2.5, 2.0, 1.5, or 1, or any range derivabletherein). For example, an enteric coating may dissolve or partiallydissolve in a pH of about 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5,8.0, 8.5 or higher, or any range derivable therein.

Agents for enteric coatings are well-known in the art, and includemethacrylic acid copolymers, cellulose acetate, styrol maleic acidcopolymers, hydroxypropylmethyl cellulose acetate and shellac. Otherpolymers that may be used for enteric coating purposes includeEudragits®, such as anionic Eudragit® copolymers (e.g., Eudragit® L100and Eudragit® S100). Enteric coatings may also comprise other agents,such as an acetylated monoglyceride, such as Myvacet® distilledacetylated monoglyceride (e.g., Myvacet 5-07, 7-07, 9-08 and 9-45).Combinations of any enteric agents known in the art, including thosedescribed below, are also contemplated. Enteric agents may be combinedwith one or more additives, polymers, surfactants, time-release agents,and/or loading agents, as described herein. An enteric coating need notcoat the entire particle of an enterically coated particle: in certainembodiments, an enteric coating coats at least about 90%, 95%, 99% or100% of the particle. In certain embodiments, an enteric coating coats100% of the particle.

Suitable enteric coatings are also described, for example, in U.S. Pat.Nos. 4,311,833; 4,377,568; 4,457,907; 4,462,839; 4,518,433; 4,556,552;4,606,909; 4,615,885; 4,670,287; 5,536,507; 5,567,423; 5,591,433;5,597,564; 5,609,871; 5,614,222; 5,626,875; and 5,629,001, all of whichare incorporated herein by reference.

Other exemplary enteric agents include alkyl and hydroxyalkyl cellulosesand their aliphatic esters, e.g., methylcellulose, ethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose,hydroxyethylethylcellulose, hydroxyprophymethylcellulose,hydroxybutylmethylcellulose, hydroxypropylcellulose phthalate,hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcelluloseacetate succinate; carboxyalkylcelluloses and their salts, e.g.,carboxymethylethylcellulose; cellulose acetate phthalate; celluloseacetate trimellitate, polycarboxymethylene and its salts andderivatives; polyvinyl alcohol and its esters (e.g., polyvinyl acetatephthalate); polycarboxymethylene copolymer with sodium formaldehydecarboxylate; acrylic polymers and copolymers, e.g., methacrylicacid-methyl methacrylic acid copolymer and methacrylic acid-methylacrylate copolymer; edible oils such as peanut oil, palm oil, olive oiland hydrogenated vegetable oils; polyvinylpyrrolidone; polyethyleneglycol and its esters; and natural products such as shellac, and zein.

Other enteric agents include polyvinylacetate esters, e.g., polyvinylacetate phthalate; alkyleneglycolether esters of copolymers such aspartial ethylene glycol monomethylether ester of ethylacrylate-maleicanhydride copolymer or diethyleneglycol monomethylether ester ofmethylacrylate-maleic anhydride copolymer, N-butylacrylate-maleicanhydride copolymer, isobutylacrylate-maleic anhydride copolymer orethylacrylate-maleic anhydride copolymer; and polypeptides resistant todegradation in the gastric environment, e.g., polyarginine andpolylysine. Other suitable agents and methods to make and use suchformulations are well known to those skilled in the art (see, e.g.,Remington: The Science and Practice of Pharmacy, 19th ed. (1995) MackPublishing Company, Easton, Pa.; herein incorporated by reference).

Certain particles of the present invention may be formulated fortime-release of an opioid receptor antagonist. Time-release agents arewell-known in the art, and such formulations may comprise an additive, apolymer and/or an enteric agent, surfactant, or loading agent. Forexample, poly(caprolactone) of a variety of molecular weights (e.g.,30,000-90,000 g/mol) may be employed for this purpose. Non-polymers mayalso be used, such as tamsulosin, as described in U.S. PublishedApplication No. 2008/0113030, incorporated herein by reference.Combinations of time-release agents are also contemplated.

Loading agents may be employed to facilitate the making of particles.For example, an opioid receptor antagonist may be combined with aloading agent to produce a particle comprising the antagonist and theloading agent, such that the particle is “loaded” with the antagonist.Loading agents suitable for this purpose are well-known in the art. Forexample, loading agents comprising silica (SiO₂) may be employed.Loading agents comprising alkyl_((C≦5))-modified silica may also beused. Such products are commercially available. Combinations of loadingagents are also contemplated. Moreover, loading agents may be combinedwith one or more additives, polymers, surfactants, enteric agents, ortime-release agents.

III. Chemical Definitions

“Alkyl” refers to a univalent aliphatic hydrocarbon group which issaturated and which may be straight, branched, or cyclic having from 1to about 10 carbon atoms in the chain, and all combinations andsubcombinations of chains therein. Exemplary alkyl groups include, butare not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

“Lower alkyl” refers to an alkyl group having 1 to about 6 carbon atoms.

“Alkenyl” refers to a univalent aliphatic hydrocarbon group containingat least one carbon-carbon double bond and having from 2 to about 10carbon atoms in the chain, and all combinations and subcombinations ofchains therein. Exemplary alkenyl groups include, but are not limitedto, vinyl, propenyl, butynyl, pentenyl, hexenyl, and heptnyl.

“Alkynyl” refers to a univalent aliphatic hydrocarbon group containingat least one carbon-carbon triple bond and having from 2 to about 10carbon atoms in the chain, and combinations and subcombinations ofchains therein. Exemplary alkynyl groups include, but are not limitedto, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

“Alkylene” refers to a divalent aliphatic hydrocarbon group having from1 to about 6 carbon atoms, and all combinations and subcombinations ofchains therein. The alkylene group may be straight, branched, or cyclic.There may be optionally inserted along the alkylene group one or moreoxygen, sulfur, or optionally substituted nitrogen atoms, wherein thenitrogen substituent is an alkyl group as described previously.

“Alkenylene” refers to a divalent alkylene group containing at least onecarbon-carbon double bond, which may be straight, branched, or cyclic.Exemplary alkenylene groups include, but are not limited to, ethenylene(—CH═CH—) and propenylene (—CH═CHCH₂—).

“Cycloalkyl” refers to a saturated monocyclic or bicyclic hydrocarbonring having from about 3 to about 10 carbons, and all combinations andsubcombinations of rings therein.

The cycloalkyl group may be optionally substituted with one or morecycloalkyl-group substituents. Exemplary cycloalkyl groups include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and cycloheptyl.

“Acyl” means an alkyl-CO group wherein alkyl is as previously described.Exemplary acyl groups include, but are not limited to, acetyl,propanoyl, 2-methylpropanoyl, butanoyl, and palmitoyl.

“Aryl” refers to an aromatic carbocyclic radical containing from about 6to about 10 carbons, and all combinations and subcombinations of ringstherein. The aryl group may be optionally substituted with one or two ormore aryl group substituents. Exemplary aryl groups include, but are notlimited to, phenyl and naphthyl.

“Aryl-substituted alkyl” refers to a linear alkyl group, preferably alower alkyl group, substituted at a terminal carbon with an optionallysubstituted aryl group, preferably an optionally substituted phenylring. Exemplary aryl-substituted alkyl groups include, for example,phenylmethyl, phenylethyl, and 3(4-methylphenyl)propyl.

“Heterocyclic” refers to a monocyclic or multicyclic ring systemcarbocyclic radical containing from about 4 to about 10 members, and allcombinations and subcombinations of rings therein, wherein one or moreof the members of the ring is an element other than carbon, for example,nitrogen, oxygen, or sulfur. The heterocyclic group may be aromatic ornonaromatic. Exemplary heterocyclic groups include, for example, pyrroleand piperidine groups.

“Halo” refers to fluoro, chloro, bromo, or iodo.

Compounds employed in methods of the invention (e.g., opioid receptorantagonists) may contain one or more asymmetrically-substituted carbonor nitrogen atoms, and may be isolated in optically active or racemicform. Thus, all chiral, diastereomeric, racemic form, epimeric form, andall geometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.Compounds may occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Insome embodiments, a single diastereomer is obtained. The chiral centersof the compounds of the present invention can have the S- or theR-configuration, as defined by the IUPAC 1974 Recommendations. Compoundsmay be of the D- or L-form, for example. It is well known in the art howto prepare and isolate such optically active forms. For example,mixtures of stereoisomers may be separated by standard techniquesincluding, but not limited to, resolution of racemic form, normal,reverse-phase, and chiral chromatography, preferential salt formation,recrystallization, and the like, or by chiral synthesis either fromchiral starting materials or by deliberate synthesis of target chiralcenters.

In addition, atoms making up the compounds of the present invention areintended to include all isotopic forms of such atoms. Isotopes, as usedherein, include those atoms having the same atomic number but differentmass numbers. By way of general example and without limitation, isotopesof hydrogen include tritium and deuterium, and isotopes of carboninclude ¹³C and ¹⁴C.

Compounds of the invention also encompass their salts. The term“salt(s)” as used herein, is understood as being acidic and/or basicsalts formed with inorganic and/or organic acids and bases. Zwitterions(internal or inner salts) are understood as being included within theterm “salt(s)” as used herein, as are quaternary ammonium salts, such asalkylammonium salts. Some embodiments contemplate nontoxic,pharmaceutically acceptable salts as described herein, although othersalts may be useful, as, for example, in isolation or purificationsteps. Salts include, but are not limited to, sodium, lithium,potassium, amines, tartrates, citrates, hydrohalides, phosphates and thelike.

The compounds employed in methods of the invention may exist in prodrugform. As used herein, “prodrug” is intended to include any covalentlybonded carriers which release the active parent drug or compounds thatare metabolized in vivo to an active drug or other compounds employed inthe methods of the invention in vivo when such prodrug is administeredto a subject. Since prodrugs are known to enhance numerous desirablequalities of pharmaceuticals (e.g., solubility, bioavailability,manufacturing, etc.), the compounds employed in some methods of theinvention may, if desired, be delivered in prodrug form. Thus, theinvention contemplates prodrugs of compounds of the present invention aswell as methods of delivering prodrugs. Prodrugs of the compoundsemployed in the invention may be prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound.

Accordingly, prodrugs include, for example, compounds described hereinin which a hydroxy, amino, or carboxy group is bonded to any group that,when the prodrug is administered to a subject, cleaves to form a freehydroxyl, free amino, or carboxylic acid, respectively. Other examplesinclude, but are not limited to, acetate, formate, and benzoatederivatives of alcohol and amine functional groups; and alkyl,carbocyclic, aryl, and alkylaryl esters such as methyl, ethyl, propyl,iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl,benzyl, and phenethyl esters, and the like.

IV. Methods of Administration and Other Formulation Considerations

Pharmaceutical compositions of the present invention comprise aneffective amount of one or more candidate substances (e.g., a particleof the present invention) or additional agents dissolved or dispersed ina pharmaceutically acceptable carrier. The preparation of apharmaceutical composition that contains at least one candidatesubstance or additional active ingredient will be known to those ofskill in the art in light of the present disclosure, as exemplified byRemington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company,1990, incorporated herein by reference. Moreover, for animal (e.g.,human) administration, it will be understood that preparations shouldmeet sterility, pyrogenicity, general safety and purity standards asrequired by FDA Office of Biological Standards.

As used herein, “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, surfactants, antioxidants,preservatives (e.g., antibacterial agents, antifungal agents), isotonicagents, absorption delaying agents, salts, preservatives, drugs, drugstabilizers, gels, binders, excipients, disintegration agents,lubricants, sweetening agents, flavoring agents, dyes, such likematerials and combinations thereof, as would be known to one of ordinaryskill in the art (see, for example, Remington's Pharmaceutical Sciences,pp 1289-1329, 1990). Except insofar as any conventional carrier isincompatible with the active ingredient, its use in the therapeutic orpharmaceutical compositions is contemplated.

The candidate substance may comprise different types of carriersdepending on whether it is to be administered in solid, liquid oraerosol form, and whether it needs to be sterile for such routes ofadministration. Particles of the present invention may be administeredalone or as comprised in a composition (e.g., a pharmaceuticalcomposition) orally, intraadiposally, intraarterially, intraarticularly,intracranially, intradermally, intralesionally, intramuscularly,intranasally, intraocularally, intrapericardially, intraperitoneally,intrapleurally, intraprostaticaly, intrarectally, intrathecally,intratracheally, intraumbilically, intravaginally, intravenously,intravesicularly, intravitreally, liposomally, locally, mucosally,orally, parenterally, rectally, subconjunctival, subcutaneously,sublingually, topically, transbuccally, transdermally, vaginally, increams, in lipid compositions, via a catheter, via a lavage, viacontinuous infusion, via infusion, via inhalation, via injection, vialocal delivery, via localized perfusion, bathing target cells directly,or by other method or any combination of the foregoing as would be knownto one of ordinary skill in the art (see, for example, Remington'sPharmaceutical Sciences, 1990). In particular embodiments, a particle ofthe present invention may be formulated for oral delivery. In certainembodiments, intramuscular, intravenous, topical administration, orinhalation administration is contemplated. In certain embodiments, oraladministration is contemplated. As noted, pharmaceutical compositionscomprising a particle of the present invention are also contemplated,and such compositions may be adapted for administration via any methodknown to those of skill in the art, such as the methods described above.

In particular embodiments, a particle of the present invention orcomposition comprising such a particle is administered to a subjectusing a drug delivery device. Any drug delivery device is contemplatedin this regard.

The actual dosage amount of an opioid receptor antagonist comprised in aparticle of the present invention that is administered to a subject canbe determined by physical and physiological factors such as body weight,severity of condition, the type of disease being treated, previous orconcurrent therapeutic interventions, idiopathy of the patient and onthe route of administration. The practitioner responsible foradministration will typically determine the concentration of activeingredient(s) in a composition and appropriate dose(s) for theindividual subject.

The dose can be repeated as needed as determined by those of ordinaryskill in the art. Thus, in some embodiments of the methods set forthherein, a single dose is contemplated. In other embodiments, two or moredoses are contemplated. Where more than one dose is administered to asubject, the time interval between doses can be any time interval asdetermined by those of ordinary skill in the art. For example, the timeinterval between doses may be about 1 hour to about 2 hours, about 2hours to about 6 hours, about 6 hours to about 10 hours, about 10 hoursto about 24 hours, about 1 day to about 2 days, about 1 week to about 2weeks, or longer, or any time interval derivable within any of theserecited ranges.

In certain embodiments, it may be desirable to provide a continuoussupply of a pharmaceutical composition to the patient. This could beaccomplished by catheterization, followed by continuous administrationof the therapeutic agent, for example. The administration could beintra-operative or post-operative.

In certain embodiments, pharmaceutical compositions may comprise, forexample, at least about 0.1% of an opioid receptor antagonist. In otherembodiments, the opioid receptor antagonist may comprise between about2% to about 75% of the weight of the unit, or between about 25% to about60%, for example, and any range derivable therein. In other non-limitingexamples, a dose may also comprise from about 10 μg/kg/body weight, 100μg/kg/body weight, 200 μg/kg/body weight, 350 μg/kg/body weight, 500μg/kg/body weight, 1 mg/kg/body weight, 5 mg/kg/body weight, 10mg/kg/body weight, 50 mg/kg/body weight, to about 100 mg/kg/body weightor more of the opioid receptor antagonist per administration, or anyrange derivable therein. In a non-limiting example of a derivable rangefrom the numbers listed herein, a range of about 0.1 mg/kg/body weightto about 10 mg/kg/body weight may be administered.

In any case, the composition may comprise various antioxidants to retardoxidation of one or more component. Additionally, the prevention of theaction of microorganisms can be brought about by preservatives such asvarious antibacterial and antifungal agents, including but not limitedto parabens (e.g., methylparabens, propylparabens), chlorobutanol,phenol, sorbic acid, thimerosal, or combinations thereof.

The opioid receptor antagonist comprised in a particle may be formulatedinto a composition, such as a pharmaceutical composition, in a freebase, neutral, or salt form. Pharmaceutically acceptable salts aredescribed herein.

In embodiments wherein a carrier is employed, such a carrier may be asolvent or dispersion medium comprising but not limited to, water,ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethyleneglycol, etc.), lipids (e.g., triglycerides, vegetable oils, liposomes)and combinations thereof. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin; by the maintenanceof the required particle size by dispersion in carriers such as, forexample liquid polyol or lipids; by the use of surfactants such as, forexample hydroxypropylcellulose; or combinations thereof such methods. Itmay be preferable to include isotonic agents, such as, for example,sugars, sodium chloride, or combinations thereof.

In other embodiments, one may use eye drops, nasal solutions or sprays,aerosols or inhalants in the present invention. Such compositions aregenerally designed to be compatible with the target tissue type. In anon-limiting example, nasal solutions are usually aqueous solutionsdesigned to be administered to the nasal passages in drops or sprays.Nasal solutions are prepared so that they are similar in many respectsto nasal secretions, so that normal ciliary action is maintained. Thus,in certain embodiments the aqueous nasal solutions usually are isotonicor slightly buffered to maintain a pH of about 5.5 to about 6.5. Inaddition, antimicrobial preservatives, similar to those used inophthalmic preparations, drugs, or appropriate drug stabilizers, ifrequired, may be included in the formulation. For example, variouscommercial nasal preparations are known and include drugs such asantibiotics or antihistamines.

In certain embodiments the candidate substance is prepared foradministration by such routes as oral ingestion. In these embodiments,the solid composition may comprise, for example, solutions, suspensions,emulsions, tablets, pills, capsules (e.g., hard or soft shelled gelatincapsules), sustained release formulations, buccal compositions, troches,elixirs, suspensions, syrups, wafers, or combinations thereof. Inparticular embodiments, suspensions and capsules are contemplated. Oralcompositions may be incorporated directly with the food of the diet. Incertain embodiments, carriers for oral administration comprise inertdiluents (e.g., glucose, lactose, or mannitol), assimilable ediblecarriers or combinations thereof. In other aspects of the invention, theoral composition may be prepared as a syrup or elixir. A syrup orelixir, and may comprise, for example, at least one active agent, asweetening agent, a preservative, a flavoring agent, a dye, apreservative, or combinations thereof.

In certain embodiments an oral composition may comprise one or morebinders, excipients, disintegration agents, lubricants, flavoringagents, or combinations thereof. In certain embodiments, a compositionmay comprise one or more of the following: a binder, such as, forexample, gum tragacanth, acacia, cornstarch, gelatin or combinationsthereof; an excipient, such as, for example, dicalcium phosphate,mannitol, lactose, starch, magnesium stearate, sodium saccharine,cellulose, magnesium carbonate or combinations thereof; a disintegratingagent, such as, for example, corn starch, potato starch, alginic acid orcombinations thereof; a lubricant, such as, for example, magnesiumstearate; a sweetening agent, such as, for example, sucrose, lactose,saccharin or combinations thereof; a flavoring agent, such as, forexample peppermint, oil of wintergreen, cherry flavoring, orangeflavoring, etc.; or combinations thereof the foregoing. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, carriers such as a liquid carrier. Various other materialsmay be present as coatings or to otherwise modify the physical form ofthe dosage unit. For instance, tablets, pills, or capsules may be coatedwith shellac, sugar, or both.

Sterile injectable solutions may be prepared by incorporating a particleof the present invention in the required amount in the appropriatesolvent with various of the other ingredients enumerated above, asrequired, followed by sterilization. Generally, dispersions are preparedby incorporating the various sterilized active ingredients into asterile vehicle which contains the basic dispersion medium and/or theother ingredients. In the case of sterile powders for the preparation ofsterile injectable solutions, suspensions or emulsion, certain methodsof preparation may include vacuum-drying or freeze-drying techniqueswhich yield a powder of the active ingredient plus any additionaldesired ingredient from a previously sterilized liquid medium thereof.The liquid medium should be suitably buffered if necessary and theliquid diluent (e.g., water) first rendered isotonic prior to injectionwith sufficient saline or glucose. The preparation of highlyconcentrated compositions for direct injection is also contemplated,where the use of DMSO as solvent is envisioned to result in extremelyrapid penetration, delivering high concentrations of the active agentsto a small area.

The composition should be stable under the conditions of manufacture andstorage, and preserved against the contaminating action ofmicroorganisms, such as bacteria and fungi. It will be appreciated thatendotoxin contamination should be kept minimally at a safe level, forexample, less that 0.5 ng/mg protein.

In particular embodiments, prolonged absorption of an injectablecomposition can be brought about by the use in the compositions ofagents delaying absorption, such as, for example, aluminum monostearate,gelatin, or combinations thereof.

Certain embodiments of the present invention refer to aqueousformulations or solutions of methylnaltrexone, specifically. Suchaqueous formulations may include a chelating agent, a buffering agent,an anti-oxidant and, optionally, an isotonicity agent, and may be pHadjusted to between about 3.0-3.5.

V. Combination Therapy

In order to enhance or increase the effectiveness of an opioid receptorantagonist comprised in a particle of the present invention, theparticle may be combined with another therapy, such as another agentthat combats and/or prevents a disorder mediated by opioid receptoractivity. For example, a particle of the present invention may beprovided in a combined amount with an effective amount of a secondopioid receptor antagonist. Additionally, a particle of the presentinvention may be provided in a combined amount with an effective amountof an anti-cancer agent, as described in U.S. Patent Application No.2006/0258696, PCT Publication No. WO 06/096626, or PCT Publication No.WO 07/053,194, all hereby incorporated by reference. The second agentmay be comprised in a second particle.

It is contemplated that combination therapy of the present invention maybe used in vitro or in vivo. These processes may involve administeringthe agents at the same time or within a period of time wherein separateadministration of the substances produces a desired therapeutic benefit.This may be achieved by contacting the cell, tissue, or organism with acomposition, such as a pharmaceutically acceptable composition, thatincludes two or more agents, or by contacting the cell with two or moredistinct compositions, wherein one composition includes one agent andthe other includes another.

The particles of the present invention may precede, be co-current withand/or follow the other agents by intervals ranging from minutes toweeks. In embodiments where the agents are applied separately to a cell,tissue or organism, one would generally ensure that a significant periodof time did not expire between the time of each delivery, such that theagents would still be able to exert an advantageously combined effect onthe cell, tissue or organism. For example, in such instances, it iscontemplated that one may contact the cell, tissue or organism with two,three, four or more modalities substantially simultaneously (i.e.,within less than about a minute) as the candidate substance. In otheraspects, one or more agents may be administered about 1 minute, 5minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 2hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 22 hours, 23hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44hours, 45 hours, 46 hours, 47 hours, 48 hours, 1 day, 2 days, 3 days, 4days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days,13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days,21 days, 1, 2, 3, 4, 5, 6, 7 or 8 weeks or more, or any range derivabletherein, prior to and/or after administering the candidate substance.

Various combination regimens of the agents may be employed. Non-limitingexamples of such combinations are shown below, wherein a particle of thepresent invention is “A” and a second agent, such as a second opioidreceptor antagonist, is “B”:

A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B B/B/B/A B/B/A/BA/A/B/B A/B/A/B A/B/B/A B/B/A/A B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/AA/A/B/A

VI. Examples

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

Reagents used in each of these examples are commercially available.

Example 1 Preparation of Particles Comprising Methylnaltrexone

A procedure developed by the Alonso lab from the School of Pharmacy,University of Santiago de Compostela, Spain was employed (Calvo et al.,1997; Fernandez-Urrusuno et al., 1999).

Methylnaltrexone (MNTX) (Mallinckrodt Chemicals, St. Louis, Mo.) wasdissolved in water and then incorporated in an aqueous pentasodiumtripolyphosphate (TPP) solution. Under high-speed magnetic stirring ofan aqueous chitosan solution, the MNTX-containing TPP solution wasslowly added into the chitosan solution. Nanoparticles containing MNTXwere then formed. The final ratio of chitosan:TPP:MNTX was approximately5/1.8/3.2 (w/w/w). MNTX nanoparticles were collected by centrifugation,supernatants were discarded and the remaining nanoparticles werelyophilized.

Example 2 Preparation of Enterically Coated Particles ComprisingMethylnaltrexone

Enterically coated MNTX nanoparticles were prepared by encapsulating thenanoparticles of Example 1 with a Eudagrit® L100 and Myvacet® 9-45mixture. See, e.g., U.S. Pat. No. 6,608,075 and Yuan et al., 2000, eachof which is incorporated herein by reference in its entirety. The finalsubstance was the 30-80 mesh fraction which was 60% MNTX nanoparticlesby weight. It was shown to decrease release of the drug at gastric pH by90% based on the methods of the United States Pharmacopoeia/NationalFormulary (The United States Pharmacopeia, 1995). See also U.S. Pat. No.6,608,075 and Yuan et al., 2000.

Example 3 Preparation of a Heteroparticulate Particle ComprisingMethylnaltrexone

Methodology as described by Beck et al., 2004 was followed. To preparethe outer particles, a lipophilic solution consisting of Epikuron 170®(0.1532 g), a polymer (poly(caprolactone) (PCL) (MW=60,000 g/mol) orEudragit® 5100) (1.0 g) and acetone (267.0 ml) was used. This organicphase was added to an aqueous solution (533.0 ml) containing Tween 80®(0.1532 g) under moderate magnetic stirring. The solution wasconcentrated by evaporation under reduced pressure, and then the finalvolume was adjusted to 100 ml using acetone, corresponding to a polymerconcentration of 10 mg/ml.

To prepare the inner particle, an MNTX solution (17 mM, 50 mL) was addedto Aerosil® 200 (1.50 g). The mixture was fed into a mini-spray-dryer toproduce particles having an MNTX core (feed rate: 3.0 ml/min; air flowrate: 500 NL/hr; atomizing air pressure: 200 kPa; inlet temperature:170±4° C.; outlet temperature: 110±4° C.; nozzle diameter 0.7 mm).

The coating step was performed as follows: the MNTX particles (1.5 g)were rapidly dispersed into the outer particle suspension (50 mL) undermagnetic stirring. This mixture was spray-dried to obtainheteroparticulate particles, wherein the inner particle comprised MNTXand the outer particles that surrounded the inner particle comprised apolymer suitable as an enteric coating (spray dryer conditions: feedrate: 3.0 ml/min; air flow rate: 500 NL/hr; atomizing air pressure: 200kPa; inlet temperature: 170±4° C.; outlet temperature: 110±4° C.; nozzlediameter 0.7 mm).

This nanoparticles is pH-responsive. At pH 2.0 (in the gastricenvironment), the drug release was very low. At pH 7.4, the drug releasewas almost 100% in 15 min (The United States Pharmacopeia, 1995).

Example 4 In Vivo Study of Plasma Levels Upon Particle Administration

Abbreviations: N1-MNTX=particles of Example 2; N2-MNTX=particles ofExample 3 using PCL.

Male Wistar strain rats, weighing between 200-300 g were used. Rats ingroup 1 (n=6) received 10 mg/kg regular MNTX (in distilled water); ratsin group 2 (n=7) received 10 mg/kg N1-MNTX (in distilled water); rats ingroup 3 (n=5) received 10 mg/kg N2-MNTX (in solution with pH 2). Drugswere administered orally via a gavage tube in the morning at time 0.There were 6-8 rats per group.

Blood samples were collected from the tail vein for the measurement ofplasma MNTX levels. The samples were typically collected every 30 min.from time 0 to time 360 min. Plasma MNTX levels were determined by highperformance liquid chromatography (HPLC) adapted from a previouslyreported method (Osinski et al., 2002). The practical limit of detectionfor plasma samples was approximately 2 ng/mL (100 pg/injection).

MNTX plasma levels after oral administration of MNTX, N1-MNTX andN2-MNTX to rats are shown in FIG. 1. Absorption of MNTX in both of theMNTX particle formulations (N1-MNTX and N2-MNTX) into the blood streamof rats was much more efficient than the absorption of aqueous MNTX. Thechitosan/TPP/MNTX formulation (N1-MNTX) proved to be more efficient thanthe Epikuron 170® formulation (N2-MNTX), however both performed muchbetter than non-particulate MNTX. These results demonstrate thatparticle formulations of methylnaltrexone and other opioid antagonistscan greatly increase the absorption of these compounds into the centralnervous system of mammals, thus decreasing the dose required to reachtherapeutic plasma levels.

REFERENCES

The following references, to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

-   U.S. Pat. No. 3,723,440-   U.S. Pat. No. 4,176,186-   U.S. Pat. No. 4,311,833-   U.S. Pat. No. 4,377,568-   U.S. Pat. No. 4,457,907-   U.S. Pat. No. 4,462,839-   U.S. Pat. No. 4,518,433-   U.S. Pat. No. 4,556,552-   U.S. Pat. No. 4,606,909-   U.S. Pat. No. 4,615,885-   U.S. Pat. No. 4,670,287-   U.S. Pat. No. 4,719,215-   U.S. Pat. No. 4,861,781-   U.S. Pat. No. 5,102,887-   U.S. Pat. No. 5,270,328-   U.S. Pat. No. 5,536,507-   U.S. Pat. No. 5,567,423-   U.S. Pat. No. 5,591,433-   U.S. Pat. No. 5,597,564-   U.S. Pat. No. 5,609,871-   U.S. Pat. No. 5,614,222-   U.S. Pat. No. 5,626,875-   U.S. Pat. No. 5,629,001-   U.S. Pat. No. 5,972,954-   U.S. Pat. No. 6,274,591-   U.S. Pat. No. 6,451,806-   U.S. Pat. No. 6,469,030-   U.S. Pat. No. 6,608,075-   U.S. Published Appl. 2002/0028825-   U.S. Published Appl. 2003/0022909-   U.S. Published Appl. 2006/0105046-   U.S. Published Appl. 2006/0258696-   U.S. Published Appl. 2008/0064744-   U.S. Published Appl. 2008/0113030-   Beck et al., J Microencapsulation, 21:499-512, 2004.-   Calvo et al., J Appl Pol Sci., 63:125-32, 1997.-   Fernandez-Urrusuno et al., Pharm Res., 16:1576-81, 1999.-   Handbook of Pharmaceutical Salts: Properties, Selection and Use    (Stahl and Wermuth, Eds.), Verlag Helvetica Chimica Acta, 2002.-   Osinski et al., J Chromatogr B, 780:251-9, 2002.-   PCT Appln. WO 06/096626-   PCT Appln. WO 07/053,194-   PCT Appln. WO 98/25613-   PCT Appln. WO 99/22737-   Remington's: The Science and Practice of Pharmacy, 19^(th) Ed., Mac    Publishing Co., Easton, Pa., 1676-1692, 1995.-   Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company,    1289-1329, 1990.-   Sarmento et al., Biomacromolecules, 8:3054-60, 2007.-   The United States Pharmacopeia: The National Formulary. Rockville:    United States Pharmacopeial Convention, Inc, 1793-1799, 1995.-   Yuan et al., Clin. Pharmacol. Ther., 61:467-475, 1997-   Yuan et al., Clin. Pharmacol. Ther., 67:398-404, 2000.

1. A particle comprising an opioid receptor antagonist and at least oneadditive, wherein the diameter of the particle is between about 30-1000nm.
 2. The particle of claim 1, wherein the at least one additive is apolymer.
 3. (canceled)
 4. The particle of claim 1, wherein the opioidreceptor antagonist is a peripheral opioid antagonist.
 5. The particleof claim 1, wherein the opioid receptor antagonist is a quaternary ortertiary morphinan derivative, a piperidine-N-alkylcarboxylate, acarboxy-normorphinan derivative, or a quaternary benzomorphan.
 6. Theparticle of claim 5, wherein the quaternary morphinan is a quaternarysalt of N-methylnaltrexone, N-methylnaloxone, N-methylnalorphine,N-diallylnormorphine, N-allyllevellorphan, or N-methylnalmefene.
 7. Theparticle of claim 5, wherein the peripheral opioid receptor antagonistis methylnaltrexone. 8-12. (canceled)
 13. The particle of claim 1,wherein at least one additive is a hydrophilic additive.
 14. Theparticle of claim 13, wherein the particle comprises at least twohydrophilic additives.
 15. The particle of claim 13, wherein onehydrophilic additive is positively charged at acidic and neutral pH. 16.The particle of claim 15, wherein the hydrophilic additive that ispositively charged at acidic and neutral pH is further defined aschitosan.
 17. The particle of claim 13, wherein one hydrophilic additiveis negatively charged at acidic and neutral pH.
 18. The particle ofclaim 17, wherein the hydrophilic additive that is negatively charged atacidic and neutral pH is further defined as pentasodium tripolyphosphate(TPP). 19-20. (canceled)
 21. The particle of claim 14, wherein the twohydrophilic additives are further defined as chitosan and TPP. 22-26.(canceled)
 27. The particle of claim 1, wherein the particle iscomprised in an enteric coating to form an enterically coated particle,wherein the enterically coated particle has a diameter of about 30-1000nm. 28-32. (canceled)
 33. The particle of claim 27, wherein the entericcoating comprises both a Eudragit® polymer and a Myvacet™ distilledacetylated monoglyceride. 34-35. (canceled)
 36. A pharmaceuticalcomposition comprising the particle of claim 1 and a pharmaceuticallyacceptable carrier. 37-40. (canceled)
 41. The pharmaceutical compositionof claim 36, further defined as a time release pharmaceuticalcomposition, wherein the time release pharmaceutical composition isformulated to release the opioid receptor antagonist over time.
 42. Apharmaceutical composition comprising the enterically coated particle ofclaim 27 and a pharmaceutically acceptable carrier. 43-52. (canceled)53. A method of making a plurality of particles of claim 1, wherein eachparticle comprises an opioid receptor antagonist, the method comprising:(a) dissolving an opioid receptor antagonist in water to form adissolved opioid receptor antagonist solution; (b) adding the dissolvedopioid receptor antagonist solution to a solution comprising a firstadditive to form an opioid receptor antagonist/first additive solution;and (c) adding the opioid receptor antagonist/first additive solution toa solution comprising a second additive, such that the plurality ofparticles is made. 54-57. (canceled)
 58. A heteroparticulate particlecomprising: (a) an inner, larger particle comprising an opioid receptorantagonist; and (b) an outer, smaller particle comprising at least onesurfactant and at least one additive, wherein the diameter of the outerparticle is between about 100-500 nm.
 59. The heteroparticulate particleof claim 58, wherein the opioid receptor antagonist is a quaternarymorphinan.
 60. The heteroparticulate particle of claim 59, wherein thequaternary morphinan is further defined as methylnaltrexone.
 61. Theheteroparticulate particle of claim 58, wherein the inner, largerparticle is further defined as a microparticle.
 62. Theheteroparticulate particle of claim 58, wherein the inner, largerparticle of part (a) further comprises a loading agent. 63-65.(canceled)
 66. The heteroparticulate particle of claim 58, wherein theouter, smaller particle is formulated as an enteric coating. 67-73.(canceled)
 74. A heteroparticulate particle comprising: (a) an innerphase comprising one larger particle, wherein the larger particlecomprises an opioid receptor antagonist and a loading agent; and (b) anouter phase comprising a plurality of smaller particles, wherein eachsmaller particle comprises Epikuron 170®, Tween® 80, apoly(caprolactone) polymer and a Eudragit® polymer.
 75. Theheteroparticulate particle of claim 74, wherein the opioid receptorantagonist is further defined as methylnaltrexone. 76-127. (canceled)